The preponderance of annual mortality in the Western world is caused by atherosclerosis, which often presents as cerebrovascular accident or myocardial infarction. Unfortunately, comprehensive evaluation of atherosclerosis generally ensues only after a clinical event is caused by plaque rupture in the later stages of this disease process.
The close association of angiogenesis with atherosclerosis disease is recognized. See, for example, O'Brien et al. (1994) Am. J. Pathol. 145:883-894. Angiogenesis is a critical feature of plaque development in atherosclerosis and may play a key role in both the initiation of plaque development and the later rupture of plaques leading to myocardial infarction and stroke. In atherosclerotic disease, angiogenic vessels primarily develop from the vasa vasorum in the adventitial layer of the plaque and extend into the thickening intimal layer of the atheroma rather than originating from the primary arterial lumen. Extensive neovascular proliferation has been spatially localized to atherosclerotic plaque, and in particular, to “culprit” lesions clinically associated with unstable angina, myocardial infarction and stroke. Plaque angiogenesis appears to play a role in promotion of plaque growth, intraplaque hemorrhage, and lesion instability. See, for example, Zhang et al. (1993) Am. J. Pathol. 143:164-172; Tenaglia et al. (1998) Am. Heart J. 135:10-14; Moulton (2002) Cold Spring Harb. Symp. Quant. Biol. 67:471-482.
Paramagnetic nanoparticles targeted to αvβ3-integrins, an angiogenic biomarker expressed by proliferating neovasculature, can provide sensitive and specific detection and characterization of early atherosclerosis in hypercholesterolemic rabbits. See, for example, Winter et al. (2003) Circulation 108:2270-2274; Brooks et al. (1994) Cell. 79:1157-1164. Such imaging data reaffirmed the diffuse nature of the early atherosclerotic process and illustrated the considerable heterogeneity of disease found within individual aortic segments.
When administered chronically at high dosages, anti-angiogenic agents, such as endostatin and TNP-470, a water soluble form of fumagillin, have shown some activity for decreasing neovascular proliferation and plaque growth in animal models of early atherosclerosis (Wilson et al. (2002) Circulation 105:415-418; Moulton et al. (1999) Circulation 99:1726-1732). For example, Apo E−/− mice treated for 4 months (20 to 36 weeks) with TNP-470 or endostatin had reduced number of intimal vessels and diminished atheroma expansion despite elevated total cholesterol levels. Neither endostatin nor TNP-470 altered foam cell deposition or fibromuscular lesion development during early atherogenesis, and they were both less effective during later periods of treatment (32 to 48 weeks) (Moulton et al. (1999) Supra). Unfortunately, high dose TNP-470 has serious side effects such as neurocognitive toxicity (Herbst et al. (2002) J. Clin. Oncol. 20:4440-4447.
There is a continuing need for the development of methods and compositions that are effective in specifically reaching and reducing unwanted neovasculature, including that associated with atherosclerosis.
All publications and patent applications cited herein are hereby incorporated by reference in their entirety.